Molecular defects that affect platelet dense granules

Abstract

Platelet dense granules form using mechanisms shared by melanosomes in melanocytes and by subsets of lysosomes in more generalized cells. Consequently, disorders of platelet dense granules can reveal how organelles form and move within cells. Models for the study of new vesicle formation include isolated delta-storage pool deficiency, combined alphadelta-storage pool deficiency, Hermansky-Pudlak syndrome (HPS), Chediak-Higashi syndrome, Griscelli syndrome, thrombocytopenia absent radii syndrome, and Wiskott-Aldrich syndrome. The molecular bases of dense granule deficiency are known for the seven subtypes of HPS, as well as for Chediak-Higashi syndrome, Griscelli syndrome, and Wiskott-Aldrich syndrome. The gene products involved in these disorders help elucidate the generalized process of the formation of vesicles from extant membranes such as the Golgi.

Figure 1

Electron microscopy of platelets showing presence and absence of dense bodies. (A) Whole-mount electron microscopy showing dark, electron-dense granules in the platelets of a 45-year-old woman with albinism but not Hermansky-Pudlak syndrome (HPS). (B) Whole-mount electron microscopy showing absence of dense bodies in the platelets of a 34-year-old man with HPS-1. (C) Transmission electron microscopy showing dense bodies (arrows) in the platelet of a patient with gray platelet syndrome. Note absence of α-granules. (D) Transmission electron microscopy showing absence of dense bodies in a platelet from a 30-year-old woman with HPS-1. Double arrow points to α-granules. (Photographs courtesy of Dr. James G. White, University of Minnesota.)

Figure 2

Hair of three HPS patients, all of Puerto Rican ancestry. (A) Typical gray-brown hair of a 54-year-old man with HPS-1. (B) Completely white hair of a 4-year-old boy with HPS-1. (C) Nearly normal, dark hair of a 5-year-old girl with HPS-3.

Figure 3

Intracellular distribution of LAMP3 and F-actin in normal, Hermansky-Pudlak syndrome (HPS)-1, HPS-3, and HPS-5 fibroblasts. Fibroblasts were fixed on coverslips and stained with mouse monoclonal antibodies to LAMP3 (as described in Huizing et al) and F-actin (Phalloidin, Molecular Probes, Eugene, OR). F-actin staining (red) was employed to mark the outline of the cells, in particular the dendritic tips. Insets show isolated dendritic tips. (A) Normal fibroblasts show a punctate LAMP3 (green) distribution throughout the cell, including at the ends of the dendritic tips. (B) HPS-1 fibroblasts show a clumped accumulation of LAMP3 in the perinuclear area. (C) HPS-3 fibroblasts appear to have a nearly normal LAMP3 distribution, with LAMP3 reaching into the dendritic tips. (D) HPS-5 cells have minimal LAMP3 transport into the tips, but LAMP3 does not accumulate in clumps in the perinuclear area, as in HPS-1. (Photographs produced by Heidi Dorward.)